A. Field of the Invention
The present invention relates generally to cyclic fused beta-lactones and their synthesis. Cyclic-fused beta-lactones are found in many natural products, some of which are known to have therapeutic value. Thus, in certain aspects, the compounds and syntheses of the present invention provide useful synthetic intermediates for natural product preparations. In other aspects, compounds of the present invention can be administered for therapeutic purposes.
B. Background of the Invention
In recent years, the asymmetric synthesis of beta-lactones has become an area of active research. For a review of this subject area, see: Yang and Romo, 1999; for more recent advances, see: Getzler et al., 2002; Zhu et al., 2004; Wilson and Fu, 2004; and Calter et al., 2005. This is due namely to the fact that these cyclic compounds are useful synthetic intermediates for natural product synthesis, are found in a growing number of bioactive natural products, and have continued potential as enzyme inhibitors and as monomers for polymer synthesis. For relevant articles regarding these topics, see: Wang et al., 2004; Lowe and Vederas, 1995; Lall et al., 2002; and Rieth et al., 2002. In particular, bicyclic-beta-lactones are structural motifs found in several natural products including Omuralide, salinosporamide, spongiolactone and the triterpenes lueolactone and papyriogenin G. For reviews of naturally occurring beta-lactones and their synthesis, see: Lowe and Vederas, 1995; and Pommier and Pons, 1995. More importantly, the presence of the beta-lactone in these bicyclics allows for facile conversion into a variety of functional arrays and thus these bicyclics may serve as useful diversity scaffolds.
The Wynberg beta-lactone synthesis was one of the first practical, catalytic asymmetric reactions developed and its utility was demonstrated by the fact that Lonza Ltd. employed this process for the large-scale synthesis of optically active malic and citramalic acids (Wynberg and Staring, 1982; Wynberg, 1986). Limitations to the Wynberg procedure are the need for a ketene generator and the requirement of activated (i.e. typically beta-dihalogenated) aldehyde substrates. In early studies by Wynberg, it was determined that at least two beta-halogen atoms were required (see: Wynberg and Staring, 1985. For other activated carbonyl compounds that participate in this reaction, see: Ramiandrasoa et al., 1993).
The inventors previously developed an intramolecular, catalytic, asymmetric, nucleophile catalyzed aldol-lactonization (NCAL) process of aldehyde acids that leads to a variety of novel, carbocycle-fused beta-lactone systems. Cortez et al., 2001. This represented the first example of a catalytic, asymmetric NCAL reaction with unactivated (i.e. non-chlorinated) aldehydes and this methodology merges catalytic, asymmetric beta-lactone synthesis with carbocycle construction employing an organic catalyst. Only carbocyclic compounds were produced via this procedures. A need exists, however, to extend this methodology to other substrates besides aldehyde acids, particularly more tractable substrates such as keto acids. Moreover, synthetic routes for producing heteroatom-containing products are needed as well.